Methods and apparatus for intraluminal deposition of hydrogels

ABSTRACT

Methods and apparatus of forming hydrogel systems in situ are provided using a delivery system configured to deliver two or more fluent prepolymer solutions without premature crosslinking. The delivery system comprises separate first and second lumens coupling first and second inlet ports and first and second outlet ports, respectively, and may include a balloon, flexible distal region, mixing chamber or steerable distal end. Multi-component hydrogel systems suitable for use with the inventive methods and apparatus are also described.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.09/390,046 filed Sep. 3, 1999, now issued as U.S. Pat. No. 6,379,373,which is a Continuation-In-Part of U.S. patent application Ser. No.09/133,950 filed Aug. 14, 1998, now issued as U.S. Pat. No. 6,152,943,which are hereby incorporated by reference herein.

FIELD OF THE INVENTION

This present invention relates to methods and apparatus for applyinghydrogels within body lumens to occlude, coat or support tissue. Moreparticularly, the present invention relates apparatus and methods forintraluminally delivering two or more liquid components to form ahydrogel implant in situ.

BACKGROUND OF THE INVENTION

Hydrogels are materials that absorb solvents (such as water), undergorapid swelling without discernible dissolution, and maintainthree-dimensional networks capable of reversible deformation. See, e.g.,Park, et al., Biodegradable Hydrogels for Drug Delivery, Technomic Pub.Co., Lancaster, Pa. (1993).

Hydrogels may be uncrosslinked or crosslinked. Uncrosslinked hydrogelsare able to absorb water but do not dissolve due to the presence ofhydrophobic and hydrophilic regions. A number of investigators haveexplored the concept of combining hydrophilic and hydrophobic polymericcomponents in block (Okano, et al., “Effect of Hydrophilic andHydrophobic Microdomains on Mode of Interaction Between Block Polymerand Blood Platelets”, J. Biomed. Mat. Research, 15:393-402 (1981), orgraft copolymeric structures (Onishi, et al., in Contemporary Topics inPolymer Science, (Bailey & Tsuruta, Eds.), Plenum Pub. Co., New York,1984, p. 149), and blends (Shah, “Novel two-phase polymer system,”Polymer, 28:1212-1216 (1987) and U.S. Pat. No. 4,369,229 to Shah) toform the “hydrophobic-hydrophilic” domain systems, which are suited forthermoplastic processing. See, Shah, Chap. 30, in Water Soluble Polymers(Shalaby et al., Eds.), Vol. 467, ACS-Symp. Ser., Amer. Chem. Soc.,Washington (1991). These uncrosslinked materials can form hydrogels whenplaced in an aqueous environment.

Covalently crosslinked networks of hydrophilic polymers, includingwater-soluble polymers are traditionally denoted as hydrogels (oraquagels) in the hydrated state. Hydrogels have been prepared based oncrosslinked polymeric chains of methoxypoly(ethylene glycol)monomethacrylate having variable lengths of the polyoxyethylene sidechains, and their interaction with blood components has been studied(Nagaoka et al., in Polymers as Biomaterial (Shalaby et al., Eds.)Plenum Press, 1983, p. 381). A number of aqueous hydrogels have beenused in various biomedical applications, such as, for example, softcontact lenses, wound management, and drug delivery.

Non-degradable hydrogels made from poly(vinyl pyrrolidone) andmethacrylate have been fashioned into fallopian tubal occluding devicesthat swell and occlude the lumen of the tube. See, Brundin, “HydrogelTubal Blocking Device: P-Block”, in Female Transcervical Sterilization,(Zatuchini et al., Eds.) Harper Row, Philadelphia (1982). Because suchhydrogels undergo a relatively small amount of swelling and are notabsorbable, so that the sterilization is not reversible, the devicesdescribed in the foregoing reference have found limited utility.

It therefore would be desirable to provide methods and apparatus ofusing hydrogel materials to temporarily occlude a body lumen thatovercome the drawbacks of previously known compositions and methods.

Abnormal vascular connections, known as arteriovenous malformations(AVMs), may develop either as a congenital defect or as a result ofiatrogenic or other trauma. An AVM may lead to a substantial diversionof blood from the intended tissue and may consequently engender avariety of symptoms, including those leading to morbidity. Subduralhematomas and bleeding also may occur as a result of the presence of anAVM.

Surgical intervention is often undertaken to correct AVMs.Interventional radiologic approaches also are used to obliterate AVMs byembolization, in which the goal of embolization is to selectivelyobliterate an abnormal vascular structure, while preserving blood supplyto surrounding normal tissue. Embolization typically is accomplishedusing low-profile soft microcatheters that allow superselectivecatheterization into the brain to deliver an embolic material underfluoroscopic guidance. Various embolic materials have been used inendovascular treatment in the central nervous system, such ascyanoacrylates, ethylene-vinyl alcohol copolymer mixtures, ethanol,estrogen, poly(vinyl acetate), cellulose acetate polymer, poly (vinylalcohol), gelatin sponges, microfibrillar collagen, surgical silksutures, detachable balloons, and coils. Delivery of these embolicmaterials often requires the use of elaborate delivery systems.

It would therefore be desirable to provide methods and apparatus forusing multi-component hydrogel systems as embolic materials to occludearteriovenous malformations, thus taking advantage of the relative easewith which the crosslinkable components of a hydrogel system may bedelivered.

U.S. Pat. No. 5,785,679 to Abolfathi et al. describes methods andapparatus for excluding aneurysms with in-situ moldable agents, such aswater-swellable and thermally initiated hydrogels, by intraluminally orlaparoscopically injecting the moldable material around an inflatablemember disposed in the vessel. The reference also describes embedding astent in the moldable material for enhanced support. InternationalPublication No. WO 95/08289 describes a similar system for excludinganeurysms using photopolymerizable materials. Both systems employinflatable members that partially or completely occlude the vessel andmold the moldable material during polymerization.

It would therefore be desirable to provide methods and apparatus forexcluding aneurysms using hydrogels that are formed in situ, withoutpartially or completely occluding the vessel.

SUMMARY OF THE INVENTION

In view of the foregoing, it is an object of the present invention toprovide methods and apparatus of using hydrogel materials to temporarilyocclude a body lumen that overcome the drawbacks of previously knowncompositions and methods.

It is another object of this invention to provide methods and apparatusfor using multi-component hydrogel systems as embolic materials toocclude arteriovenous malformations, thus taking advantage of therelative ease with which the crosslinkable components of a hydrogelsystem may be delivered.

It is a further object of the present invention to provide methods andapparatus for excluding aneurysms using hydrogels that are formed insitu, without partially or completely occluding the vessel.

These and other objects of the invention are accomplished by providingapparatus and methods for delivering and applying crosslinkablecompositions (referred to herein as “prepolymers”) to selected tissuelumens, and then initiating a reaction in situ by allowing theprepolymers to either mix with other prepolymers and initiate acrosslinking process, or to be exposed to the physiological environmentto initiate the crosslinking process. The crosslinkable solutions usedwith the apparatus may be crosslinked using either physicalcrosslinking, chemical crosslinking, or both.

In accordance with the present invention, delivery systems are providedfor delivering separate prepolymer components of a hydrogel system,without premature crosslinking within the delivery system. In oneembodiment, the delivery system includes an occlusive element foranchoring a distal end and isolating the region in which the hydrogel isto be formed in situ. In another embodiment, the delivery system mayinclude variable stiffness regions to enable passage through tortuousanatomy. In yet another embodiment, the delivery system includes asteerable tip. In still further alternative embodiments, the prepolymercomponents of the hydrogel system may be mixed together in a mixingchamber disposed in a distal region of the delivery system, and thenextruded into the body lumen or void during the crosslinking process, toreduce washout or dilution of the components.

Methods of using the inventive apparatus to apply a polymeric materialto a lumen as a coating, or to fill in a luminal defect, such as ananeurysm, to occlude an abnormal vascular structure, such as anarteriovenous malformation or arteriovenous fistula whether natural orinduced, and to occlude a natural lumen for a therapeutic purpose,within a human or animal patient, also are provided.

BRIEF DESCRIPTION OF THE DRAWINGS

Further features of the invention, its nature and various advantageswill be more apparent from the accompanying drawings and the followingdetailed description of the preferred embodiments, in which:

FIGS. 1A and 1B are, respectively, a side view and cross-sectional view,taken along view line 1B—1B, of a delivery system constructed inaccordance with the present invention for injecting two in situcrosslinkable components to occlude a body lumen or arteriovenousmalformation;

FIG. 2 illustrates a method of using the apparatus of FIG. 1 to occludefallopian tubes;

FIG. 3 is a side view, partly in section, of a delivery system of thepresent invention having a flexible distal region and mixing chamber;

FIG. 4 is a side view of a delivery system of the present inventionhaving a steerable tip; and

FIGS. 5A and 5B illustrate a method of using the apparatus of FIG. 4 toexclude an aneurysm.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to methods and apparatus forintraluminally delivering two or more crosslinkable solutions to formhydrogel implants in situ. The following written description describesmulti-component hydrogel systems suitable for such use, delivery systemsfor depositing such hydrogel systems, and provides illustrative examplesof use of the inventive apparatus and methods.

Hydrogel Systems Suitable For Use

Crosslinkable solutions preferred for use in accordance with theprinciples of the present invention include those that may be used toform implants in lumens or voids, and may form physical crosslinks,chemical crosslinks, or both. Physical crosslinks may result fromcomplexation, hydrogen bonding, desolvation, Van der Waals interactions,ionic bonding, etc., and may be initiated by mixing two components thatare physically separated until combined in situ, or as a consequence ofa prevalent condition in the physiological environment, such astemperature, pH, ionic strength, etc. Chemical crosslinking may beaccomplished by any of a number of mechanisms, including free radicalpolymerization, condensation polymerization, anionic or cationicpolymerization, step growth polymerization, etc. Where two solutions areemployed, each solution preferably contains one component of aco-initiating system and crosslink on contact. The solutions areseparately stored and mix when delivered into a tissue lumen.

Hydrogels suitable for use in accordance with the principles of thepresent invention preferably crosslink spontaneously without requiringthe use of a separate energy source. Such systems allow good control ofthe crosslinking process, because gelation does not occur until thecatheter is actuated and mixing of the two solutions takes place. Ifdesired, one or both crosslinkable solutions may contain contrast agentsor other means for visualizing the hydrogel implant. Alternatively, acolored compound may be produced as a byproduct of the reactive process.The crosslinkable solutions also may contain a bioactive drug ortherapeutic compound that is entrapped in the resulting implant, so thatthe hydrogel implant serves a drug delivery function.

Properties of the hydrogel system, other than crosslinkability,preferably should be selected according to the intended application. Forexample, if the hydrogel implant is to be used to temporarily occlude areproductive organ, such as a fallopian tube, it is preferable that thehydrogel system undergo significant swelling and be biodegradable.Alternatively, the hydrogel may have thrombotic properties, or itscomponents may react with blood or other body fluids to form a coagulum.

Other applications may require different characteristics of the hydrogelsystem. There is extensive literature describing the formulation ofcrosslinkable materials for particular medical applications, whichformulae may be readily adapted for use herein with littleexperimentation. More generally, the materials should be selected on thebasis of exhibited biocompatibility and lack of toxicity. Also, thehydrogel solutions should not contain harmful or toxic solvents.

Additionally, the hydrogel system solutions should not contain harmfulor toxic solvents. Preferably, the solutions are substantially solublein water to allow application in a physiologically-compatible solution,such as buffered isotonic saline. Water-soluble coatings may form thinfilms, but more preferably form three-dimensional gels of controlledthickness. It is also preferable in cases that the coating bebiodegradable, so that it does not have to be retrieved from the body.Biodegradability, as used herein, refers to the predictabledisintegration of the coating into molecules small enough to bemetabolized or excreted under normal physiological conditions.

Polymers Suitable for Physical Crosslinking

Physical crosslinking may be intramolecular or intermolecular or in somecases, both. For example, hydrogels can be formed by the ionicinteraction of divalent cationic metal ions (such as Ca+2 and Mg+2) withionic polysaccharides such as alginates, xanthan gums, natural gum,agar, agarose, carrageenan, fucoidan, furcellaran, laminaran, hypnea,eucheuma, gum arabic, gum ghatti, gum karaya, gum tragacanth, locustbeam gum, arabinogalactan, pectin, and amylopectin. These crosslinks maybe easily reversed by exposure to species that chelate the crosslinkingmetal ions, for example, ethylene diamine tetraacetic acid.Multifunctional cationic polymers, such as poly(1-lysine),poly(allylamine), poly(ethyleneimine), poly(guanidine), poly(vinylamine), which contain a plurality of amine functionalities along thebackbone, may be used to further induce ionic crosslinks.

Hydrophobic interactions are often able to induce physical entanglement,especially in polymers, that induces increases in viscosity,precipitation, or gelation of polymeric solutions. For example,poly(oxyethylene)-poly(oxypropylene) block copolymers, available underthe trade name of PLURONIC®, BASF Corporation, Mount Olive, N.J., arewell known to exhibit a thermoreversible behavior in solution. Thus, anaqueous solution of 30% PLURONIC® F-127 is a relatively low viscosityliquid at 4° C. and forms a pasty gel at physiological temperatures dueto hydrophobic interactions. Other block and graft copolymers of watersoluble and insoluble polymers exhibit similar effects, for example,copolymers of poly(oxyethylene) with poly(styrene), poly(caprolactone),poly(butadiene) etc.

Techniques to tailor the transition temperature, i.e. the temperature atwhich an aqueous solution transitions to a gel due to physical linking,are per se known. For example, the transition temperature may be loweredby increasing the degree of polymerization of the hydrophobic graftedchain or block relative to the hydrophilic block. Increase in theoverall polymeric molecular weight, while keeping the hydrophilic:lipophilic ratio unchanged also leads to a lower gel transitiontemperature, because the polymeric chains entangle more effectively.Gels likewise may be obtained at lower relative concentrations comparedto polymers with lower molecular weights.

Solutions of other synthetic polymers such as poly(N-alkylacrylamides)also form hydrogels that exhibit thermoreversible behavior and exhibitweak physical crosslinks on warming. During deposition ofthermoreversible solutions, the solutions may cooled so that, uponcontact with tissue target at physiological temperatures, viscosityincreases as a result of the formation of physical crosslinks.Similarly, pH responsive polymers that have a low viscosity at acidic orbasic pH may be employed, and exhibit an increase in viscosity uponreaching neutral pH, for example, due to decreased solubility.

For example, polyanionic polymers such as poly(acrylic acid) orpoly(methacrylic acid) possess a low viscosity at acidic pHs thatincreases as the polymers become more solvated at higher pHs. Thesolubility and gelation of such polymers further may be controlled byinteraction with other water soluble polymers that complex with thepolyanionic polymers. For example, it is well known that poly(ethyleneoxides) of molecular weight over 2,000 dissolve to form clear solutionsin water. When these solutions are mixed with similar clear solutions ofpoly(methacrylic acid) or poly(acrylic acid), however, thickening,gelation, or precipitation occurs depending on the particular pH andconditions used (for example see Smith et al., “Association reactionsfor poly(alkylene oxides) and poly(carboxylic acids),” Ind Eng. Chem.,51:1361 (1959). Thus, a two component aqueous solution system may beselected so that the first component (among other components) consistsof poly(acrylic acid) or poly(methacrylic acid) at an elevated pH ofaround 8-9 and the other component consists of (among other components)a solution of poly(ethylene glycol) at an acidic pH, such that the twosolutions on being combined in situ result in an immediate increase inviscosity due to physical crosslinking.

Physical gelation also may be obtained in several naturally existingpolymers too. For example gelatin, which is a hydrolyzed form ofcollagen, one of the most common physiologically occurring polymers,gels by forming physical crosslinks when cooled from an elevatedtemperature. Other natural polymers, such as glycosaminoglycans, e.g.,hyaluronic acid, contain both anionic and cationic functional groupsalong each polymeric chain. This allows the formation of bothintramolecular as well as intermolecular ionic crosslinks, and isresponsible for the thixotropic (or shear thinning) nature of hyaluronicacid. The crosslinks are temporarily disrupted during shear, leading tolow apparent viscosities and flow, and reform on the removal of shear,thereby causing the gel to reform.

Macromers Suitable for Chemical Crosslinking

Water soluble polymerizable polymeric monomers having a functionality>1(i.e., that form crosslinked networks on polymerization) and that formhydrogels are referred to hereinafter as “macromers”.

Several functional groups may be used to facilitate chemicalcrosslinking reactions. When these functional groups are selfcondensible, such as ethylenically unsaturated functional groups, thecrosslinker alone is sufficient to result in the formation of ahydrogel, when polymerization is initiated with appropriate agents.Where two solutions are employed, each solution preferably contains onecomponent of a co-initiating system and crosslink on contact. Thesolutions are stored in separate compartments of a delivery system, andmix either when deposited on or within the tissue.

An example of an initiating system suitable for use in the presentinvention is the combination of a peroxygen compound in one solution,and a reactive ion, such as a transition metal, in another. Other meansfor crosslinking macromers to form tissue implants in situ also may beadvantageously used, including macromers that contain groups thatdemonstrate activity towards functional groups such as amines, imines,thiols, carboxyls, isocyanates, urethanes, amides, thiocyanates,hydroxyls, etc., which may be naturally present in, on, or aroundtissue. Alternatively, such functional groups optionally may be providedin the lumen as part of the hydrogel system.

Preferred hydrogel systems are those biocompatible multi-componentsystems that spontaneously crosslink when the components are mixed, butwherein the two or more components are individually stable. Such systemsinclude, for example, contain macromers that are di or multifunctionalamines in one component and di or multifunctional oxirane containingmoieties in the other component. Other initiator systems, such ascomponents of redox type initiators, also may be used. The mixing of thetwo or more solutions may result in either an addition or condensationpolymerization that further leads to the formation of an implant.

Monomers

Any monomer capable of being crosslinked to form a biocompatible implantmay be used. The monomers may be small molecules, such as acrylic acidor vinyl caprolactam, larger molecules containing polymerizable groups,such as acrylate-capped polyethylene glycol (PEG-diacrylate), or otherpolymers containing ethylenically-unsaturated groups, such as those ofU.S. Pat. No. 4,938,763 to Dunn et al, U.S. Pat. Nos. 5,100,992 and4,826,945 to Cohn et al, U.S. Pat. Nos. 4,741,872 and 5,160,745 to DeLuca et al., or U.S. Pat. No. 5,410,016 to Hubbell et al.

Preferred monomers are the biodegradable, water-soluble macromersdescribed in U.S. Pat. No. 5,410,016 to Hubbell et al., which isincorporated herein by reference. These monomers are characterized byhaving at least two polymerizable groups, separated by at least onedegradable region. When polymerized in water, they form coherent gelsthat persist until eliminated by self-degradation. In the most preferredembodiment, the macromer is formed with a core of a polymer that iswater soluble and biocompatible, such as the polyalkylene oxidepolyethylene glycol, flanked by hydroxy acids such as lactic acid,having acrylate groups coupled thereto. Preferred monomers, in additionto being biodegradable, biocompatible, and non-toxic, also will be atleast somewhat elastic after crosslinking or curing.

It has been determined that monomers with longer distances betweencrosslinks are generally softer, more compliant, and more elastic. Thus,in the polymers of Hubbell, et al., increased length of thewater-soluble segment, such as polyethylene glycol, tends to enhanceelasticity. Molecular weights in the range of 10,000 to 35,000 ofpolyethylene glycol are preferred for such applications, although rangesfrom 3,000 to 100,000 also are useful.

Initiating Systems

Metal ions may be used either as an oxidizer or a reductant in redoxinitiating systems. For example, ferrous ions may be used in combinationwith a peroxide or hydroperoxide to initiate polymerization, or as partsof a polymerization system. In this case, the ferrous ions serve as areductant. In other previously known initiating systems, metal ionsserve as an oxidant.

For example, the ceric ion (4+valence state of cerium) interacts withvarious organic groups, including carboxylic acids and urethanes, toremove an electron to the metal ion, and leave an initiating radicalbehind on the organic group. In such a system, the metal ion acts as anoxidizer. Potentially suitable metal ions for either role are any of thetransition metal ions, lanthanides and actinides, which have at leasttwo readily accessible oxidation states.

Preferred metal ions have at least two states separated by only onedifference in charge. Of these, the most commonly used areferric/ferrous; cupric/cuprous; ceric/cerous; cobaltic/cobaltous;vanadate V vs. IV; permanganate; and manganic/manganous. Peroxygencontaining compounds, such as peroxides and hydroperoxides, includinghydrogen peroxide, t-butyl hydroperoxide, t-butyl peroxide, benzoylperoxide, cumyl peroxide, etc. may be used.

Thermal initiating systems may be used rather than the redox-typesystems described hereinabove. Several commercially available lowtemperature free radical initiators, such as V-044, available from WakoChemicals USA, Inc., Richmond, Va., may be used to initiate free radicalcrosslinking reactions at body temperatures to form hydrogel implantswith the aforementioned monomers.

Delivery Systems For Forming Hydrogel Implants In Situ

Referring to FIGS. 1A and 1B, an illustrative delivery systemconstructed in accordance with the principles of the present inventionis described. Delivery system 10 comprises multi-lumen catheter 11having proximal end 12 and distal end 13. Proximal end 12 includes inletports 14 and 15 coupled to respective outlet ports 16 and 17 disposednear tip 18 via separate lumens 19 and 20, respectively. Guidewire inletport 21 and balloon inflation port 22 are coupled via separate lumens 23and 24, respectively, to guidewire outlet port 25 and balloon 26.

Radio-opaque marker band 27 is disposed within balloon 26, or elsewhereon distal end 13, to assist in positioning distal end 13 of deliverysystem 10 within a body lumen under fluoroscopic guidance. Guidewire 30extends through guide wire inlet port 21 and outlet port 25, and may beused, for example, to intraluminally guide tip 18 of delivery system 10to a treatment site, such as a fallopian tube or a peripheral orcoronary artery. Balloon 26 may be inflated to anchor catheter 11 inposition within a body lumen during formation of a hydrogel implant, andmay also occlude a lumen to prevent fluid flow from diluting theprepolymer solutions during gelation. Delivery system 10 optionally mayinclude an outer sheath that surrounds balloon 26 when the balloon isdeflated.

Alternatively, catheter 11 may be configured to have only three lumens,for example, lumens 19, 23 and 24 of the embodiment of FIG. 1B, thusomitting inlet port 15 and outlet port 17. In this case, lumen 19couples inlet port 14 to outlet port 16, lumen 23 couples guidewireinlet port 21 to outlet port 25, and lumen 24 couples inflation port 22to the interior of balloon 26. In operation, lumen 23 initially may beused to position the delivery catheter 10 in a desired position, andguidewire 30 is then withdrawn. A first crosslinkable solution is theninjected through lumen 23 while a second crosslinkable solution isinjected through lumen 19. The crosslinkable solutions crosslink whenmixed to form a hydrogel implant.

As a further alternative to the embodiment of FIG. 1, guidewire lumen 23need not extend the length of the catheter to form a so-called “over thewire” catheter. Instead, guidewire lumen 23 may be configured as ashorter lumen that exits catheter 11 through a skive just proximal ofballoon 26 to form a so-called “rapid exchange” catheter, as described,for example, in U.S. Pat. No. 4,762,129 to Bonzel.

Delivery system 10 may be fabricated of any of a wide variety ofmaterials that are sufficiently flexible and biocompatible. For example,polyethylenes, nylons, polyvinylchlorides, polyether block amides,polyurethanes, and other similar materials are suitable. It is preferredthat the material have a low coefficient of friction, at least withinthe lumen 23, to facilitate movement of the delivery system overguidewire 30. Alternatively, the lumen 23 may be coated with alubricious material to lower frictional resistance between the wall oflumen 23 and guidewire 30. For example, if catheter 11 comprises aurethane, a polyethylene oxide-based material may be coated onto thelumens of the device to provide lubricity.

Balloon 26 preferably comprises a relatively compliant material toenable delivery system 10 to provide complete occlusion of a body lumenover a range of lumen diameters. In addition, compliant balloons areless likely to cause trauma to the tissue lumen, thereby reducing thepotential for complications as a result of overinflation. Suitablecompliant balloon materials include, but are not limited to, latex,urethanes, and polyether block amides.

Delivery system 10 should be of a size appropriate to facilitatedelivery, to have a minimum profile, and cause minimal trauma wheninserted and advanced to a treatment site. In an embodiment suitable forforming hydrogel implants in fallopian tubes, peripheral or coronaryvessels, delivery system 10 preferably is no larger than about 1.6 mm(0.065 inches) to allow delivery through a standard coronary guidecatheter. The device preferably also is sized to easily pass throughobstructed lesions and to be deliverable over small diameter guidewires,such as guidewires having a diameter of approximately 0.30-0.45 mm(0.012-0.018 inches), as commonly used in the coronary arteries.

A molding balloon, such as described in the abovementioned U.S. Pat. No.5,785,679 or International Publication No. WO 95/08289 optionally may besubstituted for balloon 26 where it is desired to isolate a space inwhich a hydrogel implant is to be formed. Such molding balloonspreferably comprise polyethylene terephthalates or crosslinkedpolyethylenes, which exhibit little change in diameter over a wide rangeof inflation pressures. Irradiated polyethylenes have low surface energyand therefore are also desirable to minimize the effect of the polymericmaterials sticking to the molding balloon. Alternatively, a coatinghaving low surface energy may be used to facilitate release of thepolymeric material from other balloons. Such coatings include siliconeoils, fluoropolymers, surfactants, hydrogels or other hydrophobicmaterials having low surface energy.

Since non-compliant balloons, when inflated, maintain a substantiallyconstant size regardless of internal pressure, it is preferred that inthe case of gel coating applications, such as described in U.S. Pat. No.5,328,471 to Slepian, the balloon be sized approximately 0.20-1.0 mmless than the diameter of the vessel to be treated. In this manner a gelcoating having a thickness of approximately 0.10-0.50 mm may be disposedon an interior of a lumen. Alternatively, a moderately compliantballoon, e.g., made of a urethane, a polyolefin or a nylon, may be usedto treat a wider range of vessel diameters while allowing a tailored gelthickness.

Referring now to FIG. 2, a method of using delivery system 10 of FIG. 1is described for delivering hydrogel-forming precursor materials withina fallopian tube lumen. Fallopian tubes F are accessed by passingcatheter 11 through cervix C under fluoroscopic guidance. Proximal end12 of delivery system 10 is coupled to dual syringe-type device 35having actuator 36 that allows simultaneous injection of twocrosslinkable solutions, described hereinabove. Balloon 26 may beinflated with a fluid containing a contrast agent to verify placement oftip 18.

If desired, following inflation of balloon 26, the treatment space maybe filled or flushed with a solution, such as an inert saline solution,to remove blood and other biological fluids from the treatment space.Delivery system 10 optionally may include an additional lumen to permitsuch flushing liquids to exit the treatment space. Alternatively, anon-inert solution, such as a solution containing a pharmaceuticalagent, may be injected into the treatment space.

Actuator 36 is then depressed so that the solutions are deliveredthrough outlet ports 16 and 17 within the fallopian tube distal ofballoon 26. The solutions are allowed to mix and crosslink, thus formingplug 38 that occludes the fallopian tube. Balloon 26 is then deflatedand catheter 11 withdrawn.

Referring now to FIG. 3, an alternative embodiment of a delivery systemconstructed in accordance with the principles of the present inventionis described. Delivery system 40 comprises dual-lumen catheter 41 havingproximal region 42 and flexible distal region 43. Proximal region 42includes inlet ports 44 and 45 coupled to optional mixing chamber 46 andoutlet ports 47 disposed on tip 48. One or more radio-opaque markerbands (not shown) may be disposed in distal region 43 to assist inpositioning delivery system 40 within a natural or induced body lumenunder fluoroscopic guidance. Delivery system 40 may have a very smallprofile for very small vessels, e.g., below 1.6 mm, for use incerebrovascular vessels.

Delivery system 40 is particularly suitable for use where the polymericmaterial is to be applied to a surface of a natural or induced bodylumen or void, and through which a body fluid is not flowing at veryhigh velocity. Prepolymer solutions are injected via lumens 49 and 49′into mixing chamber at a rate selected so that the prepolymer solutionsbegin crosslinking in chamber 46, with the resulting partially-formedgel being extruded through outlet ports 47 into the lumen or void. Inthis manner, wash-out or dilution of the prepolymer solutions duringdeposition is reduced or eliminated, thereby reducing the risk that theprepolymer solutions will cause embolization in other portions of, forexample, the vascular system.

Delivery system 40 therefore prevents premature crosslinking of theprepolymer solutions, while also enabling the solutions to be mixed andpartially gelled before being deposited in the body lumen or void.Delivery system may be especially useful in depositing hydrogel systemsthat form both physical and chemical crosslinks, wherein the physicalcrosslinking is accomplished by mixing the prepolymer solutions inmixing chamber 46. The partial gel extruded from mixing chamber 46through outlet ports 47 then may have sufficient mechanical integrity toremain in position in the body lumen or void during the chemicalcrosslinking process.

Alternatively, distal region 43 of delivery system 40 may comprise avery flexible material, may omit mixing chamber 46, and may have asmaller diameter than that of catheter 41. Distal region 43 may beinduction welded, bonded or glued to the distal end of catheter 41 byany one of several ways per se known. Because distal region 43 is madefrom a very flexible material, distal tip 48 may be “flow directed”(i.e., tip 48 will tend to follow the direction of fluid flow within thelumen).

In treating cerebrovascular abnormalities, such as arteriovenousmalformations or tumors, it is desirable that the vasculature beembolized only within the abnormal part of the network. This may beaccomplished by radiographically monitoring placement of tip 48, andwhen proper placement is ascertained, slowly injecting the prepolymersolutions. Upon mixing within the lumen of the vessels, crosslinkingoccurs and a hydrogel is formed that occludes the abnormal vasculature.The prepolymer solutions also may contain dissolved radio contrast agentto assist in visualizing placement of the hydrogel.

With respect to FIG. 4, a further alternative embodiment of a deliverysystem constructed in accordance with the principles of the presentinvention is described. Delivery system 50 comprises multi-lumencatheter 51 having proximal end 52 and distal end 53. Proximal end 52includes inlet ports 54 and 55 coupled to respective outlet ports 56 and57 disposed on tip 58. Guidewire inlet port 59 is coupled to guidewireoutlet port 60. Delivery system 50 may include a balloon (not shown) andone or more radio-opaque marker bands (not shown) on distal end 53 toassist in positioning and anchoring delivery system 50 within a bodylumen.

In accordance with one aspect of the present invention, tip 58 isconnected via tensioning cable 61 to axle 62 located on handle 63.Tensioning cable 61 slidingly extends through a lumen in catheter 51that is eccentric with central axis 64 of catheter 51. Thus, whentensioning cable 61 is put in tension, for example, by a predeterminedamount of rotation of axle 62, tip 58 deflects away from central axis 64a predetermined amount (as shown by dotted line 58′ in FIG. 4). Deliverysystem 50 is particularly well-suited for use in conjunction with othercommonly used intraluminal devices, such as stents, stent grafts, etc.,to manage intraluminal anomalies.

Referring now to FIGS. 5A and 5B, a method of using delivery system 50for treating aneurysms is described that overcomes some of the drawbacksof previously known methods, especially as relates to use of inflatablemembers to as molding elements.

In FIG. 5A, wire mesh stent 70, such as described in U.S. Pat. No.4,655,771 to Wallsten, is disposed in vessel V to span saccular aneurysmA and define an intraluminal space between the exterior of the stent andthe interior wall of the aneurysm. Delivery system 50 is then advancedinto the interior of stent 70, and tip 58 is deflected using tensioningcable 61, as described hereinabove, to deflect tip 58 toward theinterior surface of stent 70. Delivery system 50 is then advanced sothat tip 58 passes through the wire mesh of stent 70 and is disposedwithin the aneurysm. If a balloon is provided on distal end 53 ofdelivery system 50, it is preferably inserted through the wire mesh ofstent 70 and inflated to anchor tip 58 within the aneurysm.

Once proper placement of tip 58 of the delivery system is ascertainedunder radiographic guidance, the prepolymer solutions are injected intothe intraluminal space defined by the exterior of stent 70 and theinterior wall of aneurysm A. The prepolymer solutions preferably areselected so that they crosslink to form hydrogel 65 when mixed together.The prepolymer solutions also may have a radiographic presence to assistin visualizing gradual filling of the aneurysm. The resulting hydrogel65 preferably is sufficiently malleable that it fills the intraluminalspace defined by stent 70 without protruding through the wire mesh ofstent 70.

Upon embolization, instillation of the prepolymer solutions is stoppedand delivery system 50 is withdrawn. Any residual incompleteembolization is expected to be filled in by blood clot deposition withinthe defined space. The hydrogel also may be selected so as to promotethrombus formation, e.g., due to a physical structure or texture orentrapped bioactive compound. The prepolymer solutions also may containdissolved or dispersed therapeutic compounds that are deliveredintraluminally, in either a local or systemic fashion, by entrapmentwithin the hydrogel.

Delivery system 50 therefore advantageously permits aneurysm A to beexcluded from the flow path through vessel V, without using aninflatable member or significantly occluding flow through the vessel, asin previously known methods. Delivery system 50 and the foregoing methodalso may be advantageously used in many applications, so long as thestent or stent-graft defining the intraluminal space guides theappropriate deposition of the embolic material. Thus, for example, stent70 may comprise any of a number of permeable members such as meshes,nets, stents struts, textile knitted, woven, or felted grafts, etc.

While preferred illustrative embodiments of the invention are describedabove, it will be apparent to one skilled in the art that variouschanges and modifications may be made therein without departing from theinvention and it is intended in the appended claims to cover all suchchanges and modifications which fall within the true spirit and scope ofthe invention.

EXAMPLES Example 1 Preparation of a Metered Liquid Embolic

Previously known treatments for embolization all basically rely on bloodflow in one form or another to either react to the material or to carryit downstream to a geometric constraint, such as a tapered portion of avessel. A drawback of this approach, however, is that it is difficult toform a short site-specific occlusive plug.

Numerous instances where it is desirable to form a discrete “plug” toblock a specific region of a vessel or a specific side-branch, forexample, to treat an arterio-venous fistula (AVF) or patent ductusarteriosus (PDA). A desirable configuration would have the ability todeploy a plug in a controlled manner even in the presence of blood flowto cause embolization of the vascular defect, but low risk of accidentalembolization of other downstream structures. Physically, such materialscould be delivered via a screw-driven syringe handle that allows the twomaterials not only to be delivered equally, but also to polymerize in aslow controlled manner to allow for specific amounts to be delivered atspecific rates.

Several such mechanisms are available to control the process. In oneembodiment, a two component redox polymerizable system (using freeradical polymerizable macromers) that has limited miscibility in a warmaqueous environment may be used. Block copolymers of poly (ethyleneglycol) (PEG) and poly (propylene glycol) (PPG), such as PLURONICS®(BASF Corp., Wyondette, N.J.) may be acrylated at the end groups to formF127 diacrylate macromers. These macromers, when used in aqueoussolution in excess of approximately 15% concentration, tend to undergothermal gelation at 37° C. due to a lower critical solution temperaturetransition. These materials, even though they are aqueous solutions, donot tend to dissolve in blood at physiological temperatures within a fewseconds. This period of time is expected to be adequate for solutions ofF127 diacrylate macromers to flow and conform to the vascular defect.The presence of the other solutions, which can be co-or subsequentlyinfused, causes covalent cross-linking of the physically gelledmacromers.

For example, one material configuration would be a solution A of 20%F127 diacrylate in water with 3000 ppm hydrogen peroxide and a solutionB of 10% ferrous gluconate in water with a 30% metrizamide concentrationin solution A as a radiopacifying agent. The materials are deliveredthrough a co-axial catheter such as depicted in FIG. 1.

Alternatively, the materials could be mixed within the catheter and formthe hydrogel within the catheter, and then extruded, as described forthe embodiment of FIG. 3. This configuration allows the user to“extrude” the hydrogel from the catheter and form spaghetti-like strandsthat flow within the vessel and are interrupted by the discontinuationof infusion of one or both of the hydrogel materials. As a furtheralternative, the catheter may employ a coaxial design, with an outerextrusion projecting distal to a central extrusion.

An open system flow model was prepared using water at 37° C. at a flowrate of 80 cc/min and a pressure of 2.5 psi flowing into a bifurcatedmodel with a hemostatic valve port for access. A 3.2 F co-axial catheterwas introduced into the system through the hemostatic valve and advancedinto one branch of the bifurcation model. Approximately 0.2 cc ofsolutions A and B (as described before) were infused simultaneouslyusing a dual-syringe holder to allow equal infusion of both materialssimultaneously at a rate of approximately 10 cc/min. The solutionsimmediately gelled and adhered to the tubing wall, subsequently buildingand forming a stiff gel “plug”. A blue dye was introduced into the flowpath and showed effective blockage of flow past the “plug”. The pressureon the plug was increased to over 20 psi and did not allow flow of dyepast it.

The above-described materials and apparatus also were used in a rabbitrenal artery occlusion model in vivo. The materials were delivered tothe left renal artery of the rabbit, under fluoroscopic guidance and twoconsecutive plugs were formed. These plugs were shown to occlude flownot only into the kidney but also occluded flow between the plugs thatwere spaced apart to show that flow was indeed interrupted. The plugswere visible under fluoroscopic visualization.

Example 2 Preparation of a Diffusely Polymerizing Liquid Embolic

Occasionally a need arises for a more diffuse, deeper-reaching liquidembolic that is capable of flowing for some distance within thevasculature. The system described in this example 2 allows deepintroduction of liquid embolic materials before curing and may beespecially useful in treating hypervascular tumors (among other suchdiffuse vascular diseases, including arterio venous malformations),where it is necessary to infuse the materials as deep as possible intothe tumor vasculature, thereby embolizing all of collateral andside-branches of the effected vasculature.

In this example 2, a combination of slower polymerization and lowermaterial viscosities is provided, consisting of two PEG di-acrylate (20%3.35 da) solutions in water with 3000 ppm hydrogen peroxide and 2%Ferrous gluconate as solutions A and B, respectively, with a 30%metrizamide concentration in each solution as a radiopacifying agent.The time for gelation of the solutions after mixing is slightly greaterthan 1 second.

The solutions were introduced through a co-axial catheter with solutionA introduced through one catheter lumen and solution B introducedthrough another lumen. The materials had relatively low viscosities andmixed distal to the catheter to polymerize downstream of the catheter,until adherence of the resulting gel occurred, thereby forming a longdiffuse plug throughout the vasculature.

The materials described hereinabove also were used in an in vitroexperiment using a coaxial delivery system, wherein at the catheter tipa central extrusion projected distal to an outer extrusion, thusallowing mixing to occur downstream from the distal tip of the catheter.In order to get slightly faster polymerization, a coaxial catheter maybe used having a tip configuration where the inner lumen is recessedwithin the outer lumen or vice versa. In addition, surface coatingshaving a hydrophilic or hydrophobic nature may be used on the tip of thecatheter to prevent “fouling” of the catheter tip and may promote cleandetachment of the embolic material from the catheter. Such coatings andtechniques are well known by those familiar with such art.

Example 3 Preparation of a Bio-resorbable Liguid Embolic

In many instances, such as arterio-venous malformations (“AVM”) oraneurysm, permanent occlusion of the defect is required. However, inother situations, permanent embolization may not be desirable. This mayoccur, for example, if one needs to re-visit a partially occluded tumorbed for further therapy. Previously known treatment modalities forhyper-vascular tumor embolization, with such materials as cyanoacrylatematerials and small particle PVA, form a permanent “implant” that iseither a hard polymeric branched implant or a plurality of smallparticles inhibiting flow by hitting a geometric restraint such as atapered vessel diameter.

Because it may be necessary, however, to re-access the vessels of thetumor after they have been embolized, in case small collaterals haveformed or side-branches had not been adequately embolized. With thepreviously known treatment modalities, it would be virtually impossibleto re-canalize the tumor vasculature to continue treatment andsuccessfully de-vascularize the tumor.

In accordance with the principles of the present invention, however, aliquid embolic material may be prepared having a persistence that iscontrolled to complete resorption after a predetermined period of time(1-3 weeks). The period of persistence is selected to be just longenough to effectively “starve” the tumor of its blood supply, while notbeing so long as to allow vessel stenosis from surrounding tissuenecrosis. The disease site then may be re-accessed at a later time toevaluate and potentially repeat the liquid embolic treatment. Thus, avessel may be re-embolized in enable embolization of previouslyuntreated vessels. This procedure may be repeated a number of times,until the clinician is satisfied that the tumor has decreased to aresectable size.

A sample material configuration for use in the foregoing methodcomprises a solution A of 60% succinimidyl hydroxybutarate carboxymethyl terminated polyethylene glycol and 40% succinimidylhydroxybutarate proprionate terminated polyethylene glycol (ShearwaterPolymers, Huntsville, Ala.) in 90% pH 4 phosphate buffered saline and asolution B of 10% 8-arm 20K polyethylene glycol amine (ShearwaterPolymers, Huntsville, Ala.) in pH 9.5 borate buffered saline.

Using a distal balloon catheter such as depicted in FIG.1, thesematerials were delivered via the annular space and a resorbable “plug”was successfully formed in tubing that effectively withheldphysiological pressure and flow. The plug, if left in place in anenvironment of physiologically buffered salt solutions, is expected todissolve over a 10-14 day period into water soluble substances.

Example 4 Reversal of Occlusion

The embolic occlusion of lumens described in the foregoing example 3 maybe reversed in ways other than using an absorbable material for theembolization process. For example, previously known embolectomycatheters and artherectomy devices may also be used to remove thehydrogel embolus from within the lumen to reestablish flow through thelumen. Such reversible occlusion may also be important for achievingreversible sterilization in both male and female animals and humans.Previously known artherectomy devices, such as roto-blaters, also mayadvantageously be used to re-cannulate the lumens and reverse sterilityin such cases.

Example 5 Preparation of a Vascular Puncture Closure Material

The foregoing materials also may be used in combination with a vascularpuncture closure system to provide hemostasis after endovascularprocedures. Previously known modalities include using fibrin andcollagen based materials for hemostasis post-procedurally. For example,the Duet™ system developed Vascular Solutions, Inc., Minneapolis, Minn.,comprises a device including a balloon catheter that is introducedthrough an introducer sheath into the vessel. The distal balloon isinflated and held against the vessel wall to control hemostasis. Onceflow is stopped, fibrin materials are injected through the catheter into the annular space between the delivery system and the introducersheath. Problems arising from such systems, however, due to potentialbiocompatability of the fibrin materials, unpredictable cure rates, andpotential introduction of the fibrin material into the vascular system.

By contrast, the methods and apparatus described herein provideimmediate hemostasis using a bioabsorbable gel implant. In oneembodiment, a low-profile delivery system is provided that utilizes apiston/cylinder assembly at the proximal end and a coated expandablemesh at the distal end. The device is introduced into an introducersheath and deployed similar to an umbrella that would be propped againstthe interior of the vessel wall. The gel-forming materials then areintroduced into the patient and into the annular space between theumbrella device and the introducer sheath.

As for the embodiment of FIG. 5, the materials mix in the annular spaceand cure in place using the umbrella device as a mold, thus preventingintroduction of the embolic material into the vessel. A preferredmaterial configuration for use in this example 5 comprises a solution Aof 60% succinimidyl hydroxybutarate carboxy methyl terminatedpolyethylene glycol and 40% succinimidyl hydroxybutarate proprionateterminated poly ethylene glycol (Shearwater Polymers, Huntsville, Ala.)in 90% pH 4 phosphate buffered saline and a solution B of 10% 8-arm 20Kpoly ethylene glycol amine (Shearwater Polymers, Huntsville, Ala.) in pH9.5 borate buffered saline.

Using a 6 mm tubing as a vascular model, an experiment was performedusing preparations of the foregoing materials. The delivery device was aco-axial distal balloon catheter placed inside a 6F introducer sheath.The annular space of the catheter was used as a mixing chamber of thetwo materials, with distal flow occluded by inflation of the balloon.The materials were injected through the co-axial catheter and formed aplug in the tubing model. The balloon was deflated and the catheter wasremoved leaving the “plug” behind. The track left behind immediatelyclosed and withheld physiological pressure and flow.

An experiment was performed in an in vivo porcine femoral artery. Theanimal's femoral artery was accessed percutaneously and 7F introducerset was placed. A wire-reinforced balloon catheter was advanced into thefemoral artery past the distal tip of the introducer sheath. The balloonwas slightly inflated and drawn back to the puncture site. Theintroducer sheath was removed as the balloon was pulled to come incontact with the inner wall of the femoral artery, effectively stoppingblood flow from flowing into the track.

The two materials described hereinabove then were infused into the sideport of the introducer sheath and allowed to mix within the sheath andpolymerize. The materials also were infused as the introducer wasremoved while leaving the balloon in place to protect against downstreamembolus. The materials filled the track, spilled out from the cavity,and polymerized, thus confirming polymerization. The balloon was thendeflated and removed while holding pressure on the track site. Pressurewas released and was shown to hold during leg movement. After dissectionthe gel plug was shown to be intact and effectively stop bleeding fromthe access site.

Example 6 A Kit For Operating Room Use

A kit for use in an operating room setting was assembled. The kitconsists of two vial (West Co., Lionville, Pa.) with rubber stoppers andcrimp caps that contain component A and component B respectively.Component A and component B may be present as pre-mixed solutions thatare stable in liquid form. In this case the solutions may be sterilefiltered as aqueous solutions, and then may be filled into vials orsyringes. The vials or syringes may be aseptically packaged within asecondary pouch or vacuum formed contained. If this package is not doneaseptically, then the kit may be packaged under clean conditions andsterilized by using a radiation process to sterilize the outside of thevials.

The kit also may consist of two powder filled vials containing componentA and component B and two pre-filled syringes containing aqueousbuffered solutions appropriate for reconstitution of the powders. Thereconstitution fluids optionally may contain a radiopacifier eitherdispersed or dissolved within the solution to aid in the visualizationof the deposition of the embolic agent. The syringes containing thereconstitution fluids may be used to reconstitute the respective powdercontaining vials at the time of the interventional procedure.Preferably, the buffers are selected in such a way so as to achieve amaximum “pot life” (or useful life after constitution of the powders) ofthe powders and yet allow for rapid reaction upon mixing of the twofluids at the site of deployment.

Alternatively, the reconstitution fluids also may be filled in vialsthat are drawn up into syringes within the operating room setting. Allthe components of the kits, the two vials containing component A andcomponent B are placed in a vacuum formed insert (or other container orsimilar type well known to those familiar with the art of medicalpackaging), and sealed. This insert or pouch further may be placed in asecondary container to provide added protection of the kit frommechanical damage. The kit can then be terminally sterilized. In theevent that free radically polymerizable materials are used, ethyleneoxide sterilization of the powders is appropriate.

Example 7 Aneurysm Encasement of Stabilization

It is well known in the medical literature that cerebrovascular andother aneurysms may be stabilized internally and externally by eitherfilling the aneurysm with, or encasing it in, plastic polymerizablematerials, such as cyanoacrylates and PMMA cements. Such materials,however, have several disadvantages. For example, for externalencasement of the aneurysm, such previously known materials have a lowviscosity and do not form a coating easily. Cyanoacrylates, for example,form in brittle casings that fracture and may permit the aneurysmrupture. Such previously known materials also present toxicity problems.

It would be desirable to provide materials to encase aneurysms that areflexible, strong, rapidly polymerized, and are capable of beingintegrated with surrounding brain parenchymal tissues. In accordancewith the principles of the present invention, PEG-diacrylate typematerials of an appropriate molecular weight and concentration (such asthe redox based foaming gels of Example 1) may be used to encase ananeurysm. The material may result in either a discrete gel or a foamedgel formation. The foamed gel may encourage incorporation of the gelwithin the tissue due to its porous structure, thus providing permanentstabilization of the aneurysm. The material also may be graduallyapplied using a dual syringe and a catheter based system such asdescribed hereinabove to form an atraumatic coating.

In addition, a biocompatible fabric, such as are typically used to formsynthetic grafts, may be used as a sheet and wrapped on the outside ofan aneurysm. To address the potential that some gaps may remain aroundthe fabric, which could cause aneurysmal weakening, a polymerizablehydrogel material is injected around and in between these spaces,thereby reinforcing the aneurysm. High pressures within the vessel wouldbe held by the graft material, while the hydrogel provides a sealingaction.

For aneurysms to be stabilized from within the vessel, most embolicmaterials present the inherent danger of embolizing downstream andcausing infarcts and strokes. This danger may be minimized by the use ofappropriate catheters, but the problem still is difficult to eliminateand has a very high risk of mortality associated with it. If a stentgraft type of fabric graft material is deployed around the aneurysm andthen the embolic material (such as the PEG-DA gels) are deployed using acatheter through the fabric material, it would be possible to use thegraft material as a safety net to prevent any downstream embolization,and would result in a good filling of the aneurysm too.

What is claimed is:
 1. An apparatus for use in delivering compositionsfor sealing a puncture that passes through a patient's skin and througha wall of a lumen of an artery or vein of the patient, the apparatuscomprising: an occlusive element having a nonsealing position and asealing position, with the occlusive element being adapted to sealagainst the luminal wall of the artery or vein in the sealing positionsuch that the artery or vein lumen is sealed off from the puncture; anda delivery device comprising a first and a second inlet port fluidlyconnected to a delivery device conduit that is fluidly connected to anoutlet that is adapted to allow flowable materials introduced throughthe two inlet ports to exit the delivery device; and a first containeroperably connected to the first inlet port and a second containeroperably connected to the second inlet port with each containercontaining a flowable preparation of a material chosen from the groupconsisting of a prepolymer, a macromer, and a monomer; wherein thedelivery system is adapted to be positioned with the two inlet portsoutside of the patient while the outlet opens into the puncture and theocclusive element is in the sealing position.
 2. The apparatus of claim1 wherein the occlusive element is attached to the delivery device. 3.The apparatus of claim 1 wherein the occlusive element is a balloon. 4.The apparatus of claim 1 wherein the inlet ports are disposed on a firstportion of the delivery device that is removably attachable to a secondportion of the delivery device that has said outlet.
 5. The apparatus ofclaim 1 wherein the first container is removably attachable to thedelivery device.
 6. The apparatus of claim 1 wherein the delivery deviceconduit further comprises a mixing chamber.
 7. An apparatus for use indelivering compositions for sealing a puncture that passes through apatient's skin and through a wall of a lumen of an artery or vein of thepatient, the apparatus comprising: a delivery device comprising a fistand a second inlet port and a first and a second outlet, with a firstdelivery device conduit fluidly coupling the first inlet port to thefirst outlet port and a second delivery device conduit coupling thesecond inlet port to the second outlet port; and, an occlusive elementhaving a nonsealing position and a sealing position, with the occlusiveelement being adapted to seal against the luminal wall of the artery orvein in the sealing position such that the artery or vein lumen issealed off from the puncture; wherein the delivery system is adapted tobe positioned with the two inlet ports outside of the patient while thetwo outlets open into the puncture and the occlusive element is in thesealing position.
 8. The apparatus of claim 7 wherein the occlusiveelement is attached to the delivery device.
 9. The apparatus of claim 7wherein the occlusive element is a balloon.
 10. The apparatus of claim 7wherein the inlet ports are disposed on a first portion of the deliverydevice that is removably attachable to a second portion of the deliverydevice that has said outlets.
 11. The apparatus of claim 7 furthercomprising a first container operably connected to the first inlet portand a second container operably connected to the second inlet port witheach of the containers containing a flowable preparation of a materialchosen from the group consisting of a prepolymer, a macromer, and amonomer.
 12. A system for sealing a puncture that passes through apatient's skin and through a wall of a lumen of an artery or vein of thepatient, the apparatus comprising: a delivery device comprising twoinlet ports adapted to receive fluid into the delivery device and atleast one outlet adapted to allow fluid received into the deliverydevice via at least one of the inlet ports to exit the delivery device;a first vessel fluidly connected to one of the two inlet ports and asecond vessel fluidly connected to the other of the two inlet ports,with the first vessel holding a first prepolymer comprising at least twofunctional groups chosen from the group consisting of amines and thiolsand the second vessel holding a second prepolymer comprisingpolyethylene glycol and having at least two groups that demonstratecovalent bonding activity with the functional groups of the firstprepolymer; and an occlusive element having a nonsealing position and asealing position, with the occlusive element being adapted to sealagainst the luminal wall of the artery or vein in the sealing positionsuch that the lumen is sealed off from the puncture; wherein thedelivery system is adapted to be positioned with the two inlet portsoutside of the patient while the outlet opens into the puncture and theocclusive element is in the sealing position with the two prepolymersbeing crosslinkable with each other to form a crosslinked structure. 13.The apparatus of claim 12 wherein the occlusive element is attached tothe delivery device.
 14. The apparatus of claim 12 wherein the occlusiveelement is a balloon.
 15. The apparatus of claim 12 wherein the twoinlet ports are fluidly connected to the same outlet.
 16. The apparatusof claim 15 further wherein the delivery device further comprises amixing chamber fluidly interposed between at least one of the inletports and the outlet.
 17. The apparatus of claim 12 wherein the inletports are disposed on a first portion of the delivery device that isremovably attachable to a second portion of the delivery device that hassaid outlet.
 18. The apparatus of claim 12 wherein one of the two inletports is fluidly connected to the outlet via a first delivery deviceconduit and the second of the two inlet ports is fluidly connected to asecond outlet via a second delivery device conduit and the deliverydevice conduits are not connected to each other, wherein the deliverysystem is adapted to be positioned with the two inlet ports outside ofthe patient while the two outlets open into the puncture and theocclusive element is in the sealing position.
 19. The apparatus of claim12 wherein the first vessel is removably connectable to at least one ofthe two inlet ports.
 20. An apparatus for sealing a puncture that passesthrough a patient's skin and through a wall of a lumen of an artery orvein of the patient, the apparatus comprising: means for sealing theluminal wall of the artery or vein; means for containing a firstprepolymer comprising at least two functional groups chosen from thegroup consisting of amines and thiols; means for containing a secondprepolymer comprising polyethylene glycol and having covalent bondingmeans for covalently bonding to the functional groups of the firstprepolymer; and means for delivering the first and the secondprepolymers into the puncture when the means for sealing has sealed offthe lumen of the artery or vein from the puncture.
 21. A method ofsealing a puncture that passes through a patient's skin and through awall of a lumen of an artery or vein of the patient, the methodcomprising: providing a delivery system comprising two inlet portsadapted to receive fluid into the delivery device; at least one outletadapted to allow fluid received through at least one of the two inletports to exit the delivery device, and an occlusive element having anonsealing position and a sealing position, with the occlusive elementbeing adapted to seal against the luminal wall of the artery or vein inthe sealing position such that the lumen is sealed off from thepuncture; positioning the delivery system with the two inlet portsoutside of the patient with the outlet opening into the puncture whilethe occlusive element is in the sealing position, introducing a firstprepolymer comprising at least two functional groups chosen from thegroup consisting of amines and thiols into one of the two inlet ports;and introducing into the other inlet port a second prepolymer comprisingpolyethylene glycol and having at least two groups that demonstratecovalent bonding activity with the functional groups of the firstprepolymer with the two prepolymers being crosslinkable with each otherto form a crosslinked structure.
 22. The method of claim 21 including astep of providing the delivery system wherein the inlet ports aredisposed on a portion of the delivery system that is removablyattachable to another portion of the delivery device that has saidoutlet.
 23. A kit for sealing a puncture that passes through a patient'sskin and through a wall of a lumen of an artery or vein of the patient,the kit comprising: a delivery device comprising two inlet ports adaptedto receive fluid into the delivery device and at least one outletadapted to allow fluid received into the delivery device via at leastone of the inlet ports to exit the delivery device; a first prepolymercomprising at least two functional groups chosen from the groupconsisting of amines and thiols and a second prepolymer comprisingpolyethylene glycol and having at least two groups that demonstratecovalent bonding activity with the functional groups of the firstprepolymer; an occlusive element adapted to cooperate with the deliverydevice to seal against the luminal wall of the artery or vein such thatthe lumen is sealed off from the puncture; wherein the delivery systemis adapted to be positioned with the two inlet ports outside of thepatient while the outlet opens into the puncture and the occlusiveelement is in the sealing position with the two prepolymers beingcrosslinkable with each other to form a crosslinked structure.